Optic nerve and retinal diseases profoundly impact quality of life and overall health care burden. Demetrios Vavvas and colleagues at the Mass Eye and Ear Infirmary (MEEI) have revealed a critical redundant role of mediators of both apoptosis and necrosis in cell death in the neuroretina and optic nerve in multiple ophthalmic disease models, supporting their importance as possible drug targets. Most notably, blockade of RIP kinase 1, a regulator of necrosis, pharmacologically or by gene knockout, acts synergistically with the arrest of apoptosis by pan-caspase inhibition to achieve remarkable preservation of neuronal viability and function. Specifically, when treated with pan-caspase inhibitors, Rip3-/- mice, lacking activated RIP kinase 1, are highly resistant to photoreceptor cell loss in the setting of models of retinal detachment, retinitis pigmentosa and age related macular degeneration (AMD), and retinal ganglion cells (RGCs) loss in disease models specifically impacting inner retinal and optic nerve function. This synergistic protective effect has additionally been demonstrated in wild type mice co-dosed with RIP kinase 1 and pan-caspase inhibitors. Despite the promise of applying this newly defined dual pathway inhibition to prevalent conditions such as AMD and glaucoma, the challenges of sustained therapeutic delivery to the back of the eye, and the design of clinical trials for slowly progressing neurodegenerative diseases favors pursuit of early clinical applications to conditions with rapid onset secondary to acute, minimally progressing pathology with anticipated short treatment periods, and clear efficacy endpoints and subject recruitment criteria. One such condition is non-arteritic ischemic optic neuropathy (NAION), the most common cause of acute optic nerve related vision loss, for which there are limited therapeutic options. After an initial focal ischemia associated with reduced perfusion of the microvasculature of the optic disc, often in the setting of an anatomically susceptible disc and/or systemic hypotension, a cascade of events contributes to axonal injury and RCG endangerment, culminating in caspace-associated apoptosis. There is additional abundant corollary evidence to suggest a critical roll of RIP kinase as an ultimate contributor to RGC fate via the necrotic pathway. Vavvas et al. have demonstrated rescue of RGCs in rodents by the synergistic RIP kinase 1/pan-caspase inhibition in the setting of traumatic optic neuropathy and NMDA-associated excitotoxicity. They have further established a laser photoembolic model of NAION in the rodent, employing mesoporphyrin as a fluorophore to achieve focal microvessel disruption at the disc by targeted laser photoexcitation. In this proposal, we will characterize the mesopophyrin model in the nonhuman primate and apply robustly defined clinically relevant endpoints to evaluate the efficacy of intravitreal (IVT) co-injection of the inhibitor Nec-1 and IDN-6556, both of which have been demonstrated to be potent inhibitors of RIP kinase 1 and caspases, respectively, and to be well tolerated and bioavailable following IVT injection, with combined clinical application encompassed by MEEI intellectual property that we are partnering to advance. !